CN115368367B - 一种嘧啶酮类衍生物及其制备方法和应用 - Google Patents
一种嘧啶酮类衍生物及其制备方法和应用 Download PDFInfo
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- CN115368367B CN115368367B CN202210995232.XA CN202210995232A CN115368367B CN 115368367 B CN115368367 B CN 115368367B CN 202210995232 A CN202210995232 A CN 202210995232A CN 115368367 B CN115368367 B CN 115368367B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于生物医药技术领域，具体涉及一种嘧啶酮类衍生物及其制备方法和应用。该嘧啶酮类衍生物对磷酸二酯酶一型(PDE1)表现出良好的抑制作用，可作为磷酸二酯酶一型抑制剂应用；并且根据现有技术对磷酸二酯酶一型相关疾病的研究，本发明嘧啶酮类衍生物还可以进一步应用于肺动脉高压、特发性肺纤维化等与磷酸二酯酶一型相关疾病的治疗中，可以提供更多的可选药物，具有重要的药用价值和临床应用前景。另外的，本发明嘧啶酮类衍生物结构新颖，制备方法简单，非常适用于大规模工业生产及应用。
Description
技术领域
本发明属于生物医药技术领域。更具体地，涉及一种嘧啶酮类衍生物及其制备方法和应用。
背景技术
磷酸二酯酶(PDEs)具有水解细胞内第二信使(环磷酸腺苷cAMP或环磷酸鸟苷cGMP)的功能，降解细胞内cAMP或cGMP，从而终结这些第二信使所传导的生化作用。研究证明，cAMP和cGMP在细胞活动中具有重要的调节作用，是神经递质、激素、光和气味等物质的第二信使，广泛作用于细胞内靶器官。细胞内cAMP和cGMP浓度的调节主要由核苷酸环化酶的合成和磷酸二酯酶(PDEs)的水解作用之间的平衡决定。
PDEs在人体内分布广泛，生理作用涉及多个研究领域。近年来，PDEs作为新的治疗靶点，引起了众多学者广泛的关注，成为一个新的研究热点。PDEs在体内广泛分布，其根据蛋白质的序列相似性、酶动力学特征、调节性质、细胞组织分布和药理学性质被分为11个同工酶家族(PDE1～PDE11)。其中，PDE1被鉴定为Ca2+钙调素依赖性磷酸二酯酶(CaM-pde)，被Ca2+钙调素激活并被证明介导钙和环核苷酸信号通路。研究发现，PDE1调节的信号通路的变化和中枢神经系统有所关联，可用于调节精神失常、运动障碍、认知功能和阿尔茨海默症等；也有研究表明PDE1与心功能不全有关，可用于调节心衰、心脏重塑和功能障碍等；还有些研究表明PDE1与肺、肾脏、血液学、胃肠道、肝脏、生育力、癌症和代谢紊乱等都有所关联([1]Ren,L.；Yang,C.；Dou,Y.；Zhan,R.；Sun,Y.；Yu,Y.,MiR-541-5p Regulates LungFibrosis by Targeting Cyclic Nucleotide Phosphodiesterase 1A.Exp Lung Res2017,43(6-7),249-258.[2]Xin,W.；Li,N.；Fernandes,V.S.；Chen,B.；Rovner,E.S.；Petkov,G.V.,BK Channel Regulation by Phosphodiesterase Type 1:A NovelSignaling Pathway Controlling Human Detrusor Smooth Muscle Function.Am JPhysiol Renal Physiol 2016,310(10),F994-9.)。
目前，已有PDE1抑制剂被报道为抗肺动脉高压(PAH)的药物，但是针对PDE1抑制剂的开发研究还是比较有限，仍需提供多几种对PDE1抑制剂扩大研究和临床应用的药物选择范围。
发明内容
本发明要解决的技术问题是克服现有技术缺少PDE1抑制剂的缺陷和不足，提供一种嘧啶酮类衍生物。
本发明的目的是提供所述嘧啶酮类衍生物的制备方法。
本发明另一目的是提供所述嘧啶酮类衍生物的应用。
本发明另一目的是提供一种PDE1抑制剂。
本发明上述目的通过以下技术方案实现：
一种嘧啶酮类衍生物，具有式(I)结构：
其中，R1为单取代或多取代的氢或卤素；R2为单取代或多取代的卤素、卤代C1～3烷氧基、C1～3烷氧基或卤代C1～3烷基；R3为C1～5烷基或C3～6环烷基；X为O或NH。
优选地，所述R1为氢或单取代卤素；R2为单取代或多取代的卤素、卤代甲氧基、甲氧基或卤代甲基；R3为C1～4烷基或环戊烷基；X为O或NH。
优选地，所述R1为氢或单取代氟；R2为单取代或双取代的氟、氯、F3CO-、MeO-或F3C-；R3为异丙基、异丁基或环戊烷基；X为O或NH。
更优选地，所述嘧啶酮类衍生物具有以下任一结构：
更优选地，所述嘧啶酮类衍生物具有以下任一结构：
一种嘧啶酮类衍生物，具有以下任一结构：
所述嘧啶酮类衍生物的制备方法，反应方程式如下：
具体包括以下步骤：
S1、将2,4,6-三氯嘧啶-5-甲醛和化合物a溶于乙醇中，-78℃条件下加入三乙胺并反应完全(优选为先-78℃反应1～3h，再室温反应过夜)，去除溶剂，除杂纯化(乙酸乙酯除杂，过柱纯化)，得化合物b；
S2、将步骤S1所得化合物b溶于碱溶液中，50～70℃加热回流反应完全(优选为2～4h)，用盐酸溶液(优选为2M)调节pH为中性，析晶，后处理，得化合物c；
S3、将步骤S2所得化合物c与化合物d加入异丙醇中，加入碱性试剂，110～130℃条件下加热反应完全(优选为搅拌过夜，8～20h)，后处理(优选为加水稀释乙酸乙酯萃取，有机层用无水硫酸钠干燥，浓缩过硅胶柱纯化，洗脱液为二氯甲烷/甲醇，50:1)，得化合物e；
S4、将步骤S3所得化合物e与化合物f或碘甲烷加入DNF中，加入碳酸钾15～35℃条件下反应完全，后处理，得化合物I；
其中，所述R1、R2、R3和X与上述定义一致。
进一步地，步骤S2中，所述碱溶液的碱为氢氧化钠和氢氧化钾。更进一步地，步骤S3中，所述碱性试剂为N,N-二异丙基乙胺。
另外的，本发明还要求保护所述嘧啶酮类衍生物或其药学上可接受的盐、溶剂化物在制备PDE1抑制剂中的应用。
并且，本发明还提供了一种PDE1抑制剂，以所述嘧啶酮类衍生物或其药学上可接受的盐、溶剂化物作为主要有效成分。
另外的，本发明还提供了所述嘧啶酮类衍生物或其药学上可接受的盐、溶剂化物在制备治疗与PDE1相关疾病药物中的应用。
进一步地，所述PDE1相关疾病为肺动脉高压症、特发性肺纤维化症、肺炎、血管痴呆或阿尔茨海默症。
本发明具有以下有益效果：
本发明提供了一种嘧啶酮类衍生物，其对磷酸二酯酶一型(PDE1)表现出良好的抑制作用，可作为磷酸二酯酶一型抑制剂应用；并且根据现有技术对磷酸二酯酶一型相关疾病的研究，本发明嘧啶酮类衍生物还可以进一步应用于肺动脉高压、特发性肺纤维化等与磷酸二酯酶一型相关疾病的治疗中，可以提供更多的可选药物，具有重要的药用价值和临床应用前景。另外的，本发明嘧啶酮类衍生物结构新颖，制备方法简单，非常适用于大规模工业生产及应用。
具体实施方式
以下结合具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1嘧啶酮类衍生物化合物1的制备
所述嘧啶酮类衍生物化合物1制备的反应方程式如下：
具体包括以下步骤：
步骤S1、将起始原料2,4,6-三氯嘧啶-5-甲醛(15g，71mmol)和盐酸环戊基肼(78mmol)全部溶解于乙醇(100～150mL)中，在-78℃低温下缓慢滴加三乙胺(20mL)，低温反应2小时后移至室温反应过夜12小时；反应完全后，减压旋蒸除去溶剂，再加入乙酸乙酯复溶，抽滤除去不溶物，滤液减压旋蒸除去溶剂，过柱纯化得到棕红色固体，即为化合物1-1。
步骤S2、将步骤S1所得化合物1-1(26mmol)溶于1M氢氧化钠溶液(519mL)中，在60℃下加热回流3小时，反应结束后，用2M盐酸调pH至中性，析出白色固体，抽滤干燥后得到高产率的白色固体，即为化合物2-1。
步骤S3、室温下将步骤S2所得化合物2-1(3.5mmol)和2-(2,6-二氟苯氧基)乙烷-1-胺(4.2mmol)加入异丙醇溶液中，加入碱N,N-二异丙基乙胺(7mmol)，升温至120℃下搅拌过夜，18小时；反应体系加水稀释后用乙酸乙酯萃取三次，合并有机层，无水硫酸钠干燥后浓缩得粗产物，通过硅胶柱色谱法(二氯甲烷/甲醇，50:1)纯化得到高产率的白色固体，即为化合物1。
实施例2嘧啶酮类衍生物化合物3的制备
所所述嘧啶酮类衍生物化合物3制备的反应方程式如下：
具体包括以下步骤：
步骤S4、将实施例1所得化合物1(4mM)和苄溴(6mM)加入溶液DMF(10mL)中，添加碳酸钾(8mM)，在室温下将混合物搅拌一夜，加入水20mL和乙酸乙酯20mL，所得溶液用乙酸乙酯(3×100mL)萃取，并用饱和氯化钠盐水(3×100mL)洗涤；合并有机层，无水硫酸钠干燥后浓缩得粗产物，通过硅胶柱色谱法(石油醚/EtOAc，10:1)纯化，减压浓缩得到高产率的白色固体即为化合物3。
实施例3嘧啶酮类衍生物化合物的制备、分子结构与核磁数据
参考实施例1～2的制备方法及如下反应方程式，将S1中的环戊基肼替换为相应的盐酸肼，S3中的2-(2,6-二氟苯氧基)乙烷-1-胺替换为相应的胺化合物，S4中的苄溴替换为相应的芳基溴化物或碘甲烷，即可制备得到其他嘧啶酮类衍生物化合物。
化合物1～16的核磁数据如下：
化合物1
1H NMR(400MHz,CDCl3)δ11.26(s,1H),7.89(s,1H),7.00–6.93(m,1H),6.92–6.84(m,2H),6.44(t,J＝5.5Hz,1H),4.36(t,J＝5.1Hz,2H),3.87(dd,J＝10.6,5.3Hz,2H),2.09(dd,J＝12.7,7.2Hz,4H),2.01–1.90(m,2H),1.77–1.67(m,2H).13C NMR(126MHz,CDCl3)δ160.69,157.15(d,J＝5.2Hz),155.17(d,J＝4.8Hz),154.24,152.84,134.41*2,123.26,112.29(d,J＝5.4Hz),112.16(d,J＝5.5Hz),100.02,72.78,57.34,41.08,31.99*2,24.80*2.HRMS(ESI-TOF)m/z[M+H]+calcd for C18H19F2N5O2 376.1580,found 376.1581.
化合物2
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.06–6.98(m,1H),6.93(m,J＝8.0Hz,2H),5.40(s,1H),5.02-4.92(m,1H),4.37(t,J＝4.9Hz,2H),3.90(dd,J＝10.0,5.1Hz,2H),3.49(s,3H),2.07(dd,J＝12.9,5.6Hz,4H),1.98-1.90(m,2H),1.72–1.65(m,2H).13C NMR(126MHz,CDCl3)δ158.30,156.22(d,JC-F＝247.5Hz),156.18(d,JC-F＝247.5Hz),152.52,151.43,134.81*2,123.71(t,J＝9.4Hz),112.44(d,J＝5.4Hz),112.31(d,J＝5.4Hz),99.88,72.94,57.22,42.02,32.02*2,26.60,24.80*2.HRMS(ESI-TOF)m/z[M+H]+calcd forC19H21F2N5O2 390.1736,found 390.1738.
化合物3
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.36-7.29(m,5i),7.06-6.98(m,1H),6.98-6.88(m,2H),5.32(s,2H),5.30-5.25(m,1H),4.99(p,J＝7.6Hz,1H),4.24(t,J＝4.9Hz,2H),3.76(dd,J＝10.1,5.1Hz,2H),2.16-2.06(m,4H),2.01-1.93(m,2H),1.77-1.66(m,2H).13C NMR(126MHz,CDCl3)δ158.67(s),156.07(d,JC-F＝248.0Hz),156.03(d,JC-F＝248.0Hz),152.54,151.56,135.08(d,J＝18.5Hz),129.15*2,128.00,126.67*2,123.47,112.35(d,J＝5.4Hz),112.22(d,J＝5.4Hz),99.84,72.47,57.23,43.91,42.02,32.05*2,24.82*2.HRMS(ESI-TOF)m/z[M+H]+calcd for C25H25F2N5O2 466.2049,found 466.2048.
化合物4
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.08-7.00(m,1H),6.99-6.90(m,2H),5.42(s,1H),4.90-4.79(m,1H),4.39(t,J＝4.9Hz,2H),3.91(dd,J＝10.0,5.2Hz,2H),3.51(s,3H),1.51(d,J＝6.7Hz,6H).13C NMR(126MHz,CDCl3)δ158.29(s),156.23(d,JC-F＝247.5Hz),156.19(d,JC-F＝247.5Hz),152.51,150.92,134.84,123.73(t,J＝9.4Hz),112.39(d,J＝22.7Hz),112.39(d,J＝12.0Hz),99.90,72.94,48.40,42.01,26.60,21.82*2.HRMS(ESI-TOF)m/z[M+H]+calcd for C17H19F2N5O2 364.1580,found 364.1570.
化合物5
1H NMR(400MHz,CDCl3)δ8.00(s,1H),7.38-7.30(m,5H),7.07-6.98(m,1H),6.98-6.88(m,2H),5.32(s,2H),δ5.29(t,J＝5.0Hz,1H).4.89-4.81(m,1H),4.24(t,J＝5.0Hz,2H),3.76(dd,J＝10.1,5.2Hz,2H),1.52(d,J＝6.7Hz,6H).13CNMR(126MHz,CDCl3)δ158.66,156.10(d,JC-F＝248.0Hz),156.06(d,JC-F＝248.0Hz),152.55,151.04,135.17,135.07,134.97,129.20*2,128.06,126.73*2,123.50(t,J＝9.3Hz),112.38(d,J＝5.4Hz),112.24(d,J＝5.4Hz),99.88,72.50,48.47,43.98,42.02,21.84*2.HRMS(ESI-TOF)m/z[M+H]+calcd for C23H23F2N5O2 440.1893,found 440.1891.
化合物6
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.14(dd,J＝8.0,1.4Hz,1H),7.10(t,J＝8.4Hz,2H),7.05(dd,J＝8.1,1.7Hz,1H),7.02-6.96(m,1H),5.31(s,1H),4.88(dt,J＝13.4,6.7Hz,1H),4.31(t,J＝5.0Hz,2H),3.98(dd,J＝10.3,5.3Hz,2H),3.48(s,3H),1.53(d,J＝6.7Hz,6H).13C NMR(126MHz,CDCl3)δ158.18(s),153.04(d,JC-F＝245.1Hz),152.56,150.89,146.40(d,J＝10.6Hz),134.80,124.56(d,J＝4.0Hz),122.37(d,J＝7.0Hz),116.51(d,J＝18.3Hz),116.05(d,J＝1.3Hz),99.95,68.14,48.51,41.67,26.74,21.85*2.HRMS(ESI-TOF)m/z[M+H]+calcd for C17H20FN5O2 346.1674,found 346.1658.
化合物7
1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.14-7.05(m,2H),6.97(dddd,J＝12.6,7.8,6.4,1.7Hz,2H),5.24(s,1H),4.30(t,J＝5.0Hz,2H),3.93(dd,J＝10.1,5.3Hz,2H),3.46(s,3H),1.72(s,9H).13C NMR(126MHz,CDCl3)δ158.38,153.03(d,JC-F＝245.3Hz),152.05,151.44,151.34,146.41(d,J＝10.8Hz),133.52,124.57(d,J＝3.8Hz),122.33(d,J＝7.0Hz),116.50(d,J＝18.3Hz),116.00(d,J＝1.0Hz),101.31,67.99,59.51,41.92,29.04,26.64*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C18H22FN5O2 360.1830,found360.1825.
化合物8
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.24(td,J＝7.9,5.9Hz,1H),7.13–7.09(m,1H),7.08–6.99(m,3H),6.97–6.89(m,2H),6.85(td,J＝8.2,1.4Hz,1H),5.26(s,2H),5.23(t,J＝5.2Hz,1H),4.15(t,J＝4.9Hz,2H),3.82(dd,J＝10.1,5.1Hz,2H),1.75(s,9H).13CNMR(126MHz,CDCl3)δ163.34(d,JC-F＝247.9Hz),158.60(s),152.76(d,JC-F＝245.5Hz),151.50(s),151.16(s),146.18(d,J＝10.6Hz),137.66(d,J＝7.1Hz),133.79*2(s),130.89(d,J＝8.4Hz),124.45(d,J＝3.8Hz),122.39–122.02(m),116.44(d,J＝18.2Hz),115.45(s),115.26(d,J＝21.2Hz),113.84(d,J＝22.4Hz),101.22(s),67.60(s),59.71(s),43.54(s),41.72(s),29.10(s).HRMS(ESI-TOF)m/z[M+H]+calcd for C24H25F2N5O2 454.2049,found 434.2049.
化合物9
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.19(dd,J＝13.8,7.9Hz,1H),7.01-6.98(m,1H),6.97(d,J＝7.8Hz,1H),6.95-6.86(m,3H),6.69(dd,J＝7.0,5.6Hz,1H),6.65(dd,J＝10.3,6.7Hz,1H),5.19(s,2H),4.92(t,J＝4.6Hz,1H),3.62(dd,J＝11.0,5.3Hz,2H),3.40–3.34(m,2H),1.75(s,9H).13C NMR(126MHz,CDCl3)δ163.30(d,JC-F＝248.4Hz),158.59,151.65(d,JC-F＝239.0Hz),151.57,151.33,137.65(d,J＝7.1Hz),136.05(d,J＝11.3Hz),133.77,130.87(d,J＝8.3Hz),124.62,122.02(d,J＝2.0Hz),117.63(d,J＝6.7Hz),115.30(d,J＝21.2Hz),114.73(d,J＝18.6Hz),113.67(d,J＝22.4Hz),112.12(d,J＝2.4Hz),101.16,59.77,43.41,42.52,41.83,29.13*3.HRMS(ESI-TOF)m/z[M+H]+calcdfor C24H26F2N6O 453.2209,found 453.2209.
化合物10
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.25-7.19(m,1H),7.00-6.92(m,3H),6.88(t,J＝8.7Hz,2H),6.47-6.40(m,2H),5.20(s,2H),4.94(s,1H),3.58(dd,J＝10.9,5.3Hz,2H),3.32-3.26(m,2H),1.74(s,9H).13C NMR(101MHz,CDCl3)δ163.28(d,JC-F＝248.5Hz),158.54,156.28(d,JC-F＝236.2Hz),151.55,151.29,143.72,137.91(d,J＝6.9Hz),133.81,130.93(d,J＝8.3Hz),122.24(d,J＝2.8Hz),115.95,115.72,115.28(d,J＝21.0Hz),114.07,113.99,113.82(d,J＝22.4Hz),101.16,59.75,43.39,41.71,29.12*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C24H26F2N6O 453.2209,found 453.2208.
化合物11
1H NMR(500MHz,CDCl3)δ7.90(s,1H),7.22(dd,J＝14.2,7.1Hz,1H),7.07(dd,J＝15.2,7.5Hz,1H),6.95(dd,J＝19.3,8.2Hz,2H),6.88(d,J＝9.3Hz,1H),6.41(t,J＝8.3Hz,1H),6.24(d,J＝8.1Hz,1H),6.18(d,J＝11.4Hz,1H),5.18(s,2H),5.05(s,1H),3.60(dd,J＝10.0,4.8Hz,2H),3.31(t,J＝5.1Hz,2H),1.74(s,9H).13C NMR(126MHz,CDCl3)δ164.04(d,JC-F＝243.5Hz),163.25(d,JC-F＝248.2Hz),158.59,151.56,151.27,149.25(d,J＝10.4Hz),137.79(d,J＝7.0Hz),133.71,130.92(d,J＝8.3Hz),130.47(d,J＝10.2Hz),122.08(d,J＝2.9Hz),115.25(d,J＝21.1Hz),113.68(d,J＝22.3Hz),108.82,104.57(d,J＝21.6Hz),101.12,99.68(d,J＝25.4Hz),59.79,43.28,42.69,41.57,29.14*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C24H26F2N6O 453.2209,found 453.2210.
化合物12
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.25-7.20(m,1H),7.11(d,J＝8.6Hz,2H),6.97(dd,J＝13.6,7.9Hz,2H),6.91(d,J＝8.9Hz,1H),6.42(d,J＝8.6Hz,2H),5.21(s,2H),4.85(t,J＝4.4Hz,1H),3.59(dd,J＝10.9,5.3Hz,2H),3.30(t,J＝5.5Hz,2H),1.74(s,9H).13C NMR(101MHz,CDCl3)δ163.22(d,JC-F＝248.2Hz),158.59,151.58,151.27,146.11,137.82(d,J＝7.0Hz),133.70,130.91(d,J＝8.3Hz),129.15*2,122.68,122.11(d,J＝2.6Hz),115.22(d,J＝20.9Hz),114.02*2,113.70(d,J＝22.2Hz),101.11,59.79,43.28,42.82,41.61,29.13*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C24H26ClFN6O 469.1913,found 469.1911.
化合物13
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.26-7.19(m,1H),7.00-6.89(m,3H),6.77(d,J＝8.9Hz,2H),6.49(d,J＝8.9Hz,2H),5.19(s,2H),5.03(t,J＝4.6Hz,1H),3.76(s,3H),3.59–3.52(m,2H),3.31–3.24(m,2H),1.74(s,9H).13C NMR(101MHz,CDCl3)δ163.24(d,JC-F＝248.0Hz),158.63,152.81,151.67,151.28,141.45,137.93(d,J＝7.1Hz),133.74,130.85(d,J＝8.2Hz),122.31(d,J＝2.8Hz),115.19(d,J＝21.1Hz),114.95*2,114.69*2,113.86(d,J＝22.2Hz),101.09,59.73,55.80,43.67,43.34,41.85,29.11*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C25H29FN6O2 465.2409,found 465.2406.
化合物14
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.21(dd,J＝13.8,7.8Hz,1H),7.01(d,J＝8.6Hz,2H),6.97-6.87(m,3H),6.44(d,J＝8.9Hz,2H),5.19(s,2H),4.97(t,J＝5.0Hz,1H),3.60(dd,J＝10.9,5.4Hz,2H),3.34-3.29(m,2H),1.74(s,9H).13C NMR(126MHz,CDCl3)δ163.24(d,JC-F＝248.1Hz),158.56,151.55,151.28,146.31,140.91,137.81(d,J＝7.0Hz),133.73,130.90(d,J＝8.3Hz),122.50*2,122.08(d,J＝2.9Hz),120.67(d,JC-F＝255.3Hz),115.23(d,J＝21.1Hz),113.68(d,J＝22.2Hz),113.22*2,101.12,59.79,43.29,42.93,41.57,29.12*3.HRMS(ESI-TOF)m/z[M+H]+calcd for C25H26F4N6O2 519.2126,founvd 519.2125.
化合物15
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.38(d,J＝8.4Hz,2H),7.25-7.19(m,1H),7.00-6.87(m,3H),6.48(d,J＝8.4Hz,2H),5.20(s,2H),4.84(s,1H),3.89(s,1H),3.62(dd,J＝10.9,5.3Hz,2H),3.37(s,2H),1.75(s,9H).13C NMR(101MHz,CDCl3)δ163.29(d,JC-F＝248.6Hz),158.46,151.43,151.28,149.99,137.79(d,J＝6.9Hz),133.83,131.52,131.01(d,J＝8.3Hz),126.71,122.04(d,J＝2.6Hz),119.38(q,J＝40.3Hz),115.35(d,J＝21.1Hz),113.67(d,J＝22.2Hz),111.99*2,101.21,100.00,59.81,43.34,42.43,41.49,29.16*3.HRMS(ESI-TOF)m/z[M-H]-calcd for C25H26F4N6O 501.2031,found 501.2031.
化合物16
1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.15-7.07(m,4H),7.06-7.01(m,1H),6.99(d,J＝9.3Hz,1H),6.94(d,J＝7.6Hz,1H),6.91-6.86(m,1H),5.96(d,J＝16.0Hz,1H),5.82(d,J＝7.5Hz,1H),4.63(d,J＝16.5Hz,1H),4.24(s,1H),3.31(d,J＝11.6Hz,1H),3.02(d,J＝10.1Hz,1H),2.86(d,J＝11.7Hz,1H),2.68(t,J＝11.5Hz,1H),1.99(d,J＝12.0Hz,1H),1.72(s,9H),1.47-1.34(m,3H).13C NMR(126MHz,CDCl3)δ163.19(d,JC-F＝247.9Hz),158.84,155.81(d,JC-F＝244.3Hz),152.07,150.05,140.52,138.24,133.77,130.49,124.74,123.34,122.91,119.89,116.16,114.93,114.28,100.79,59.50,56.94,50.91,47.45,43.25,29.10*3,26.40,20.51.HRMS(ESI-TOF)m/z[M-H]-calcd for C27H30F2N6O491.2376,found 491.2375.
实施例4嘧啶酮类衍生物的活性测试
以实施例制备所得化合物1～16为测试对象，测定其对磷酸二酯酶1型的抑制活性，测试浓度为100nM和10nM，测试化合物在这两种浓度条件下对PDE1B的抑制率，即指在化合物的100纳摩尔或10纳摩尔浓度下获得的PDE1B酶的抑制率。
以实施例制备所得化合物1～16为测试对象，测定其对磷酸二酯酶1型的IC50，即半数抑制浓度。
测得结果如表1所示。
表1化合物对磷酸二酯酶1型的抑制作用
| 化合物 | 抑制率％(100nM) | 抑制率％(10nM) | IC50(nM) |
| 1 | nd | 26 | nd |
| 2 | 36 | 10 | nd |
| 3 | 70 | 32 | nd |
| 4 | 40 | 14 | nd |
| 5 | 82 | 51 | nd |
| 6 | 61 | 17 | nd |
| 7 | 17 | nd | nd |
| 8 | 91 | 49 | nd |
| 9 | 79 | 39 | 3.9 |
| 10 | 72 | nd | 7.5 |
| 11 | 89 | 39 | 4.0 |
| 12 | 81 | 40 | 6.6 |
| 13 | 83 | 30 | nd |
| 14 | 76 | 48 | 6.7 |
| 15 | 76 | nd | nd |
| 16 | 59 | nd | nd |
其中，“nd”表示“未测”。
从表1中可知，大部分的化合物对于磷酸二酯酶1型均表现出显著的抑制作用，其中化合物3、5、8、9、10、11、12、13、14、15对磷酸二酯酶1型的抑制作用尤其明显，在100nM时的抑制率都大于70％；特别是化合物9、10、11、12、14，IC50小于10nM，表现出对磷酸二酯酶1型的显著抑制作用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (5)
1.一种嘧啶酮类衍生物，其特征在于，所述嘧啶酮类衍生物具有以下结构：
2.权利要求1所述嘧啶酮类衍生物的制备方法，其特征在于，反应方程式如下：
具体包括以下步骤：
S1、将2,4,6-三氯嘧啶-5-甲醛和化合物a溶于乙醇中，-78℃条件下加入三乙胺并反应完全，去除溶剂，除杂纯化，得化合物b；
S2、将步骤S1所得化合物b溶于碱溶液中，50～70℃加热回流反应完全，调节pH为中性，析晶，后处理，得化合物c；
S3、将步骤S2所得化合物c与化合物d加入异丙醇中，加入碱性试剂，110～130℃条件下加热反应完全，后处理，得化合物e；
S4、将步骤S3所得化合物e与化合物f加入DMF中，加入碳酸钾15～35℃条件下反应完全，后处理，得化合物I。
3.一种PDE1抑制剂，其特征在于，以权利要求1所述嘧啶酮类衍生物或其药学上可接受的盐作为主要有效成分。
4.权利要求1所述嘧啶酮类衍生物或其药学上可接受的盐在制备治疗与PDE1相关疾病药物中的应用。
5.根据权利要求4所述应用，其特征在于，所述PDE1相关疾病为肺动脉高压症、特发性肺纤维化症、肺炎、血管痴呆或阿尔茨海默症。
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